Induction of beneficial immune-dependent tumor regression may well depend on successfully coordinating the complex, interdependent activities of early innate response elements with subsequent powerful adaptive immune responses. The effectiveness of such a strategy also depends on unique dynamics that occur in the tumor microenvironment such that events beneficial to the tumor are subverted while events beneficial to the host are enhanced. In this context IL-12 and IL-18 play central regulatory roles for both innate and adaptive responses, and can synergize with IL-2 in several mouse kidney cancer models for T cell-dependent antitumor and antiangiogenic events that also depend on interferon gamma and/or TNF superfamily members. CD40, a TNF superfamily receptor serves as a potent trigger for dendritic cells which provide a key interface between innate and adaptive responses. The potency of dendritic cell stimulation by agonist CD40 antibodies is enhanced when used in conjunction with IL-2 and the combination of agonist anti-CD40 plus IL-2 shows enhanced antitumor activity against metastatic kidney cancer in mice. In addition, we have found that almost all renal cell carcinomas express functional CD40 and that ligation of CD40 on the tumor cells contributes to the beneficial effects of agonist CD40 therapy in vivo. These studies show that combination approaches that target different leukocyte subsets can result in greatly enhanced antitumor responses. These effects may be further increased by targeted disruption of other events in the tumor microenvironment that directly favor tumor growth, or which may actively antagonize beneficial immune responses. In this regard, we have used hydrodynamic delivery of VEGFR, and VEGFR2 gene constructs to neutralize tumor-produced VEGF and impede tumor progression. Overall, these results suggest that combination strategies which activate appropriate immune response pathways and inhibit tumor-promoting pathways in the tumor microenvironment should lead to better therapies for cancer.